Withdrawal from opiates and cocaine causes upregulation of the noradrenergic system. My research has demonstrated a central nervous system noradrenergic modulation of cognitive flexibility in anagram problem solving. As a result, impaired cognitive flexibility due to upregulation of the noradrenergic system during opiate and cocaine withdrawal may increase maladaptive behaviors seen in withdrawal by impairing cognitive flexibility. With this proposal, we wish to explore noradrenergic modulation of cognitive flexibility in cocaine withdrawal. The long-term goal of this line of research is to guide future research into treatment of drug withdrawal based on this cognitive neuropharmacological model. Our hypothesis is that cognitive flexibility in problem solving in conditions of noradrenergic activation during cocaine withdrawal can be modified pharmacologically. Our primary specific aim is to test noradrenergic modulation of cognitive flexibility in patients withdrawing from cocaine. Initially, we will undertake a dose-response study in nonaddicted normal subjects in order to determine the optimal dose of the noradrenergic antagonist propranolol needed to modulate cognitive flexibility. We will also compare noradrenergic modulation of performance on various cognitive flexibility dependent (including anagram problem solving) and cognitive flexibility independent tasks in nonaddicted normal subjects. We will then test noradrenergic modulation of cognitive flexibility in patients withdrawing from cocaine. In normal individuals, cognitive flexibility is better after noradrenergic antagonists than after noradrenergic agonists, but no difference existed between noradrenergic antagonists and placebo. However, cocaine withdrawal upregulates the noradrenergic system sufficiently that withdrawal patients may function similarly to normal individuals receiving noradrenergic agonists. Therefore, we predict that the noradrenergic upregulation during cocaine withdrawal is sufficient that administration of noradrenergic antagonists will result in a significantly better performance on cognitive flexibility than placebo, whereas this is not observed in normal subjects. We will also compare withdrawal patients and nonaddicted normal control subjects on performance on various cognitive flexibility dependent (including anagram problem solving) and cognitive flexibility independent tasks. Future possibilities include assessment the anatomical substrate of problem solving using event-related fMRI. With better understanding of modulation of cognitive flexibility, future studies can test cocaine and opiate addicts, deriving rational pharmacotherapy for optimal treatment of drug addiction. Long-term goals include further development this model of noradrenergic modulation of cognitive flexibility and looking for potential benefits in cognitively impaired and drug-addicted patients. OSU is well equipped for these goals, including potential fMRI using the most powerful human MRI in the world, strong neuroscience and psychology programs, and an established drug addiction clinic.